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Medical microrobots have potential in surgery, therapy, imaging, and diagnostics Stephen Ornes, Science Writer

Trypanosoma brucei, the pathogen that causes sleep- experiments, through a viscous sugar solution—by whip- ing sickness, has a clever and insidious trick to help it ping a flagellum-like tail. Scientists steer it by manipulat- navigate its hosts’ innards: It changes shape depend- ing external magnetic fields. ing on its surroundings. In bodily fluids, the bacterium Nelson is among a cadre of scientists who are assumes a long and narrow shape to propel itself for- designing ever-smaller robots that have the potential ward, whipping its tail-like flagellum and spinning like to improve the precision of medicine. Broadly, the a corkscrew. In other settings and life stages, when it field of “medical microrobots” includes small devices doesn’t need motility, it shortens into a stumpy blob. from a millimeter down to a few microns. All aim to To Bradley Nelson, an engineer at ETH Zurich, the safely invade the body and improve health—by diag- T. brucei’s potentially deadly shape-shifting ability nosing or monitoring a disease, such as Alzheimer’s, in was both revelation and inspiration. “Parasites have real time, measuring glucose levels in a person with evolved these interesting strategies to survive and diabetes, sending a swarm to deliver targeted thera- move,” he says. “As an engineer, I’m not sure I’d ever pies directly to tumors, or performing delicate surgery have sat down and described something like that from perhaps in the eye or even in the brain. scratch.” His laboratory focuses on developing micro- Researchers have been chasing microrobots for robots that can navigate the human body to perform decades, but the task is more difficult than miniatur- tasks, such as delivering drugs to a tumor or mechan- izing current approaches to human-scale robots. “The ically clearing blocked blood vessels. physics changes when we go to the microscale or In July 2016, Nelson and his team introduced a nanoscale,” says Shuhei Miyashita at the University T. brucei-inspired “origami robot,” a self-folding micro- of York, in the United Kingdom. Says Nelson, “You machine, made from a hydrogel, that optimizes its have to rethink your intuition at these levels.” shape according to the viscosity and temperature For tiny devices attempting to navigate this terrain, of its environment (1). It propels itself forward—in surface area becomes more important than volume,

In 2014, researchers at ETH Zurich devised microrobots that propel themselves by twisting, something like an artificial flagellum. Researchers direct the microrobots with external magnetic fields. Reproduced with permission from ref. 12.

Published under the PNAS license.

12356–12358 | PNAS | November 21, 2017 | vol. 114 | no. 47 www.pnas.org/cgi/doi/10.1073/pnas.1716034114 Downloaded by guest on September 25, 2021 which means attraction and contact forces, such as had been 3D printed from silicone to match the adhesion, have a greater influence on movement than structure and viscosity of the real thing. Using mag- does gravity, which is almost negligible because of the netic fields, the researchers navigated the unfolded minuscule mass. As a result, building microrobots robot into the stomach, where it attached to and re- often requires counter intuitive approaches to physics moved a battery embedded in the lining. In other and material design, and it’s only in the last few years experiments, Miyashita and his collaborators showed that researchers have made proof-of-concept ad- how to navigate the surgery-performing robot to vances that could lead to useful devices. patch a small stomach wound. Nelson predicts we’ll see the first clinical applica- Miyashita says he’s continuing to work on making tions in 5–10 years. Researchers are addressing the the robot smaller. He also wants to give it the ability to challenges of small-scale engineering both by build- navigate independently. Magnetic fields offer high ing machines inspired by nature—such as Nelson’s— precision for navigation, and they’re optimal for low- and by actually coopting living microswimmers, such cost, high-precision microrobotic medicine. as bacteria, heart cells, or sperm. “Ideally,” says Miyashita, “we’dlettherobotdecide its reaction to its environment.” Instead of needing to The Locomotion Challenge be steered, the device could find its own way to its Microrobots have been a long time coming. At Cal destination by following chemical cues in the blood- Tech in 1959, physicist Richard Feynman mused on stream, for example, and complete its mission. the benefits of controlling devices at small scales. He speculated about controlling atoms and building Natural Leanings computing devices inspired by biological ideas. Many microrobot researchers aren’t just looking to Feynman shared a wild idea from his friend, the nature for inspiration; they’re harnessing the existing mathematician Albert Hibbs: “it would be interesting in surgery if you could swallow the surgeon” (2). In an article published in PNAS in 1981, Massachusetts In- “You can’t control the robot because you cannot see stitute of Technology (MIT) futurist and engineer Kim the road,” he says. “We have to get better at moving Eric Drexler described an approach to molecular ma- ” chinery that used protein molecules to build atomic- them around. scale robots (3). —Sylvain Martel Such proposals inspire science-fiction visions, but there are important caveats. In the 1966 film Fantastic tools in nature’s smallest denizens. In 2013, a group at Voyage, scientists shrink a submarine to smaller than a the Institute for Integrative Nanosciences in Dresden, red blood cell and drive it through blood vessels en Germany, debuted a device that traps bull sperm in route to the brain in an attempt to remove a life- threatening clot. The fantastical notion of shrinking magnetic nanotubes and uses the cells for propulsion people to a few microns aside, the narrative was (5); magnetic fields are used to steer. Last year, the “ physics challenged in other ways. At such a small scale same group (6) unveiled a remote-controlled sperm- ” and in a fluid as thick as blood, the shrunken subma- bot, whichcanfitonaslowspermandescortit rine’s teeny propellers wouldn’t be able to move the to an egg as a possible treatment for infertility; in a ship, for example. preprint published on the arXiv in April 2017, they Keeping such challenges in mind, researchers have described a similar nanotube sperm helmet that developed a variety of ways to move and steer may carry cancer-treating drugs (7). In 2014, researchers microrobots to their destinations. Nelson’s device from the University of Illinois at Urbana–Champaign mimics the motion of a bacterium’s flagellum and can built a device that propels itself through viscous be guided by magnetic fields. At a conference in May fluids, such as blood, using constantly contracting ’ 2016 (4), researchers in Daniela Rus s laboratory at heart cells (8). MIT, in Cambridge, introduced an origami-like robot Other recent devices deliver on Drexler’s 1981 ’ that s made of a magnetic sliver attached to a film predictions. In 2012, Shawn Douglas at Harvard made from dried pig intestines. It folds up in a pill University (now at the University of California, San to be ingested and unfolds inside the body. Fully Francisco) led the design of a device made from extended, it’s about a centimeter long. Guided by DNA, designed to autonomously respond to its en- external magnetic fields, it moves by sticking to a vironment without external steering (9). He says that surface by friction and then redistributing its weight 2012 work was a proof-of-concept model. In those to slip off. The robot could be tweaked for specific tasks, such laboratory experiments, Douglas and his team at- as performing minor surgeries in the body, says tached proteins to folded DNA in random configu- Miyashita, who worked on the device as a post- rations and showed how the molecular robot could doctoral researcher in Rus’s laboratory. It might be deliver drugs to target cells. But to be effective, the designed to patch small wounds or rescue dangerous proteins and DNA have to be oriented in particu- swallowed objects, such as batteries or glass, from a lar directions—and getting precise orientations has person’s stomach. The researchers tested its capabil- turned out to be a significant technical challenge, ities via a simulated esophagus and stomach, which Douglas says. Now, he and his team are testing

Ornes PNAS | November 21, 2017 | vol. 114 | no. 47 | 12357 Downloaded by guest on September 25, 2021 different protein–DNA orientations that may perform won’t be useful for every task, he says, but cancer useful functions in the body. therapies present some interesting possibilities. In March 2017, robotics researchers at Tohoku Cancerous tumors are riddled with hypoxic areas University, in Japan, introduced an “amoeba-like” where cells reproduce quickly, resulting in low oxy- molecular robot made of natural molecules— gen. Martel’s idea is to send harmless magnetotactic including DNA, lipids, and proteins—that changes bacteria into the tumors, loaded with trace amounts its shape in response to chemical and light cues (10). of encapsulated targeted drugs. In August 2016, he Sylvain Martel, at the Polytechnique Montr ´ealin and his team reported that when they injected drug- Canada, says that autonomy is critical to making bearing bacteria near the cancer site in mice, more than half of the microbes migrated into the heart of medical biorobots useful for applications like cancer the tumors (11), autonomously seeking hypoxic therapy. External magnetic fields have a natural limit. areas after being steered the right region with mag- While internal imaging approaches can achieve a reso- netic fields. lution of about 100 microns, the leaky blood vessels that Martel’s work combines the built-in natural navi- would offer inroads for drug delivery robots are only a gational abilities of microorganisms with knowledge “ ’ few microns in diameter. You can t control the robot about disease and targeted drugs. He hypothesizes ” “ because you cannot see the road, he says. We have to that hybrids like these, which combine the functionality ” get better at moving them around. of genetically modified microorganisms with state-of- A better strategy, Martel says, is to take advantage the-art technology, have the best chance of becom- of navigation mechanisms that already exist. In his ing part of medical treatments in the future. laboratory, he’s been investigating magnetotactic “Nature creates the right specifications,” Martel bacteria, which travel along magnetic field lines and says. “If we can exploit those, we’ll have a device that gravitate, generally, to low-oxygen areas. Such microbes behaves exactly like a nanorobot of the future.”

1 Huang HW, Sakar MS, Petruska AJ, Pane ´ S, Nelson BJ (2016) Soft micromachines with programmable motility and morphology. Nat Commun 7:12263. 2 Feynman RP (1960) There’s plenty of room at the bottom. Eng Sci 23:22–36. 3 Drexler KE (1981) Molecular engineering: An approach to the development of general capabilities for molecular manipulation. Proc Natl Acad Sci USA 78:5275–5278. 4 Miyashita S, et al. (2016) Ingestible, controllable, and degradable origami robot for patching stomach wounds. 2016 IEEE International Conference on Robotics and Automation (ICRA) (IEEE, New York), pp 909–916. 5 Magdanz V, Sanchez S, Schmidt OG (2013) Development of a sperm-flagella driven micro-bio-robot. Adv Mater 25:6581–6588. 6 Medina-S ´anchezM, Schwarz L, Meyer AK, Hebenstreit F, Schmidt OG (2016) Cellular cargo delivery: Toward assisted fertilization by sperm-carrying micromotors. Nano Lett 16:555–561. 7 Xu H, et al. (2017) Sperm-hybrid micromotor for drug delivery in the female reproductive tract. arXiv:170308510 [physics, q-bio]. Available at: http://arxiv.org/abs/1703.08510. Accessed August 14, 2017. 8 Williams BJ, Anand SV, Rajagopalan J, Saif MTA (2014) A self-propelled biohybrid swimmer at low Reynolds number. Nat Commun 5:3081. 9 Douglas SM, Bachelet I, Church GM (2012) A logic-gated nanorobot for targeted transport of molecular payloads. Science 335:831–834. 10 Sato Y, Hiratsuka Y, Kawamata I, Murata S, Nomura SM (2017) Micrometer-sized molecular robot changes its shape in response to signal molecules. Sci Robot 2:eaal3735. 11 Felfoul O, et al. (2016) Magneto-aerotactic bacteria deliver drug-containing nanoliposomes to tumour hypoxic regions. Nat Nanotechnol 11:941–947. 12 Peters C, et al. (2014) Superparamagnetic twist-type actuators with shape-independent magnetic properties and surface functionalization for advanced biomedical applications. Adv Funct Mater 24:5269–5276.

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